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Richard M. Eglen - One of the best experts on this subject based on the ideXlab platform.
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Muscarinic Receptors and gastrointestinal tract smooth muscle function
Life Sciences, 2001Co-Authors: Richard M. EglenAbstract:Over the last decade, several lines of evidence have shown that both Muscarinic M2 and M3 Receptors are postjunctionally expressed in many smooth muscles, including the gastrointestinal tract. Although in vitro data suggests that both Receptors are functional in that they inhibit adenylate cyclase activity and activate non-selective cation channels, few studies support a role in vivo. Thus, data from procedures that ablate the signaling pathway of the Muscarinic M2 Receptor, including Receptor antagonism, pertussis toxin pretreatment reveal little effect on gastrointestinal smooth muscle responsiveness to Muscarinic agonists. Recently, information from knockout mice, lacking either M2 or M3 Receptor, indicate reveal a role for both subtypes. However, the contribution of the M2 Receptor appears greater in the ileum than in the urinary bladder. Therapeutically, non-selective, as well as selective M3 Receptor antagonists are being clinically studied, although it remains to be shown which is the optimal approach to disorders of smooth muscle motility.
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functional interactions between Muscarinic M2 Receptors and 5 hydroxytryptamine 5 ht 4 Receptors and β adrenoceptors in isolated oesophageal muscularis mucosae of the rat
British Journal of Pharmacology, 1996Co-Authors: Richard M. Eglen, B Peelle, M T Pulidorios, E LeungAbstract:1. Relaxations of isolated oesophageal muscularis mucosae of rat are mediated by 5-hydroxytryptamine (5-HT), acting at 5-HT4 Receptors, and isoprenaline, principally acting via beta 3-adrenoceptors. The aim of this study was to investigate the hypothesis that Muscarinic M2 Receptors, also present in this tissue, functionally oppose 5-HT and beta-adrenoceptor-relaxant effects in this preparation. 2. Contractions of rat oesophageal muscularis mucosae were induced, in a concentration-dependent manner, by the Muscarinic Receptor agonist, oxotremorine M (pEC50 = 6.7 +/- 0.1). The contractile responses to oxotremorine M were surmountably antagonized by the following compounds, (pKB values in parentheses): atropine (9.1 +/- 0.2), 4-DAMP (4-diphenylacetoxy-N-methyl piperidine methiodide, 8.7 +/- 0.1), p-F-HHSiD (para-fluoro-hexa-hydro-siladifenidol, 7.5 +/- 0.1), zamifenacin (8.6 +/- 0.3), himbacine (7.2 +/- 0.2), pirenzepine (6.8 +/- 0.3) and methoctramine (6.2 +/- 0.2). These data are consistent with a role for Muscarinic M3 Receptors mediating contractions to oxotremorine M. The contractile response was associated with a low Receptor reserve, since the responses were shifted to the right and virtually abolished by the alkylating agent, 4-DAMP mustard (4-diphenylacetoxy-N-(2-chloroethyl) piperidine, 40 nM; 60 min equilibration). 3. In tissues precontracted with U46619 (0.7 microM; approx. EC90), isoprenaline (pEC50 = 8.0 +/- 0.1) and 5-HT (pEC50 = 7.5 +/- 0.2) induced concentration-dependent relaxations. The isoprenaline potency was slightly, but significantly, different in tissues precontracted with oxotremorine M (isoprenaline, pEC50 = 7.4 +/- 0.2). In contrast, the potency of 5-HT (pEC50 = 7.5 +/- 0.2), in tissues that were precontracted with 1 microM (EC90) oxotremorine M, was identical. When these experiments were repeated in the presence of the Muscarinic M2 Receptor antagonist, methoctramine (1 microM), there was no effect on the relaxant potencies to either 5-HT or isoprenaline. Collectively, these data suggest that Muscarinic M2 Receptors do not, under these conditions, modulate relaxant potencies to either 5-HT or isoprenaline. 4. In a second protocol, tissues were pre-contracted with U46619 (0.7 microM) and relaxed with either 5-HT (0.1 microM) or isoprenaline (0.1 microM). In these tissues (in which the Muscarinic M3 Receptor population was extensively depleted by alkylation), oxotremorine M caused concentration-dependent re-contractions (i.e. reversal of relaxations). In tissues relaxed with 5-HT, the potency of oxtremorine M was 5.9 +/- 0.2, while in tissues relaxed with isoprenaline, the potency (pEC50) = 5.6 +/- 0.3. These re-contractions were antagonized, in a surmountable fashion, by methoctramine (1 microM; pKB = 7.6 +/- 0.1). Similar observations were seen when relaxations were induced by isoprenaline (1 microM; pKB = 7.5 +/- 0.2). Under these conditions, therefore, the pKB values are consistent with activation of Muscarinic M2 Receptors, and inconsistent with activation of M3 Receptors. 5. It is concluded that in isolated oesophageal muscularis mucosae of rat, Muscarinic M3 Receptors mediate direct contractions and are associated with a low Receptor reserve. When this population is depleted, and the tissues relaxed via activation of Receptors that augment adenylyl cyclase activity, a functional role for Muscarinic M2 Receptors is revealed.
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Characterization of Muscarinic Receptor and β-adrenoceptor interactions in guinea-pig oesophageal muscularis mucosae
European journal of pharmacology, 1995Co-Authors: Nikki Watson, Helen Reddy, Richard M. EglenAbstract:Abstract Smooth muscles of a number of species contain both Muscarinic M2 and M3 Receptors in differing proportions and while Muscarinic M3 Receptors mediate contraction, the role of Muscarinic M2 Receptors is unclear. Muscarinic M2 Receptor-mediated inhibition of adenylyl cyclase activity has been demonstrated in smooth muscle and since β-adrenoceptor relaxation of this tissue is mediated via stimulation of adenylyl cyclase, an interaction between Muscarinic M2 Receptors and β-adrenoceptors in smooth muscle has been postulated. Such an interaction has been demonstated in guinea-pig ileum and trachea using two different approaches. The present study investigates whether interactions between Muscarinic M2 Receptors and β-adrenoceptors also occur in guinea-pig oesophageal muscularis mucosae. Using the technique of selective Muscarinic M3 Receptor alkylation, we were unable to demonstrate Muscarinic M2 Receptor-mediated re-contractions in oesophageal smooth muscle, as described previously in ileum. In addition, while increased functional antagonism of relaxant responses to isoprenaline could be demonstrated in tissues pre-contracted with oxotremorine M compared to histamine, Muscarinic M2 Receptor activation did not contribute to this effect, as described previously in trachea. These data suggest a lack of interaction between Muscarinic M2 Receptors and β-adrenoceptors in guinea-pig oesophageal smooth muscle, but suggest an interaction between Muscarinic M3 Receptors and β-adrenoceptors.
E Leung - One of the best experts on this subject based on the ideXlab platform.
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functional interactions between Muscarinic M2 Receptors and 5 hydroxytryptamine 5 ht 4 Receptors and β adrenoceptors in isolated oesophageal muscularis mucosae of the rat
British Journal of Pharmacology, 1996Co-Authors: Richard M. Eglen, B Peelle, M T Pulidorios, E LeungAbstract:1. Relaxations of isolated oesophageal muscularis mucosae of rat are mediated by 5-hydroxytryptamine (5-HT), acting at 5-HT4 Receptors, and isoprenaline, principally acting via beta 3-adrenoceptors. The aim of this study was to investigate the hypothesis that Muscarinic M2 Receptors, also present in this tissue, functionally oppose 5-HT and beta-adrenoceptor-relaxant effects in this preparation. 2. Contractions of rat oesophageal muscularis mucosae were induced, in a concentration-dependent manner, by the Muscarinic Receptor agonist, oxotremorine M (pEC50 = 6.7 +/- 0.1). The contractile responses to oxotremorine M were surmountably antagonized by the following compounds, (pKB values in parentheses): atropine (9.1 +/- 0.2), 4-DAMP (4-diphenylacetoxy-N-methyl piperidine methiodide, 8.7 +/- 0.1), p-F-HHSiD (para-fluoro-hexa-hydro-siladifenidol, 7.5 +/- 0.1), zamifenacin (8.6 +/- 0.3), himbacine (7.2 +/- 0.2), pirenzepine (6.8 +/- 0.3) and methoctramine (6.2 +/- 0.2). These data are consistent with a role for Muscarinic M3 Receptors mediating contractions to oxotremorine M. The contractile response was associated with a low Receptor reserve, since the responses were shifted to the right and virtually abolished by the alkylating agent, 4-DAMP mustard (4-diphenylacetoxy-N-(2-chloroethyl) piperidine, 40 nM; 60 min equilibration). 3. In tissues precontracted with U46619 (0.7 microM; approx. EC90), isoprenaline (pEC50 = 8.0 +/- 0.1) and 5-HT (pEC50 = 7.5 +/- 0.2) induced concentration-dependent relaxations. The isoprenaline potency was slightly, but significantly, different in tissues precontracted with oxotremorine M (isoprenaline, pEC50 = 7.4 +/- 0.2). In contrast, the potency of 5-HT (pEC50 = 7.5 +/- 0.2), in tissues that were precontracted with 1 microM (EC90) oxotremorine M, was identical. When these experiments were repeated in the presence of the Muscarinic M2 Receptor antagonist, methoctramine (1 microM), there was no effect on the relaxant potencies to either 5-HT or isoprenaline. Collectively, these data suggest that Muscarinic M2 Receptors do not, under these conditions, modulate relaxant potencies to either 5-HT or isoprenaline. 4. In a second protocol, tissues were pre-contracted with U46619 (0.7 microM) and relaxed with either 5-HT (0.1 microM) or isoprenaline (0.1 microM). In these tissues (in which the Muscarinic M3 Receptor population was extensively depleted by alkylation), oxotremorine M caused concentration-dependent re-contractions (i.e. reversal of relaxations). In tissues relaxed with 5-HT, the potency of oxtremorine M was 5.9 +/- 0.2, while in tissues relaxed with isoprenaline, the potency (pEC50) = 5.6 +/- 0.3. These re-contractions were antagonized, in a surmountable fashion, by methoctramine (1 microM; pKB = 7.6 +/- 0.1). Similar observations were seen when relaxations were induced by isoprenaline (1 microM; pKB = 7.5 +/- 0.2). Under these conditions, therefore, the pKB values are consistent with activation of Muscarinic M2 Receptors, and inconsistent with activation of M3 Receptors. 5. It is concluded that in isolated oesophageal muscularis mucosae of rat, Muscarinic M3 Receptors mediate direct contractions and are associated with a low Receptor reserve. When this population is depleted, and the tissues relaxed via activation of Receptors that augment adenylyl cyclase activity, a functional role for Muscarinic M2 Receptors is revealed.
M T Pulidorios - One of the best experts on this subject based on the ideXlab platform.
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functional interactions between Muscarinic M2 Receptors and 5 hydroxytryptamine 5 ht 4 Receptors and β adrenoceptors in isolated oesophageal muscularis mucosae of the rat
British Journal of Pharmacology, 1996Co-Authors: Richard M. Eglen, B Peelle, M T Pulidorios, E LeungAbstract:1. Relaxations of isolated oesophageal muscularis mucosae of rat are mediated by 5-hydroxytryptamine (5-HT), acting at 5-HT4 Receptors, and isoprenaline, principally acting via beta 3-adrenoceptors. The aim of this study was to investigate the hypothesis that Muscarinic M2 Receptors, also present in this tissue, functionally oppose 5-HT and beta-adrenoceptor-relaxant effects in this preparation. 2. Contractions of rat oesophageal muscularis mucosae were induced, in a concentration-dependent manner, by the Muscarinic Receptor agonist, oxotremorine M (pEC50 = 6.7 +/- 0.1). The contractile responses to oxotremorine M were surmountably antagonized by the following compounds, (pKB values in parentheses): atropine (9.1 +/- 0.2), 4-DAMP (4-diphenylacetoxy-N-methyl piperidine methiodide, 8.7 +/- 0.1), p-F-HHSiD (para-fluoro-hexa-hydro-siladifenidol, 7.5 +/- 0.1), zamifenacin (8.6 +/- 0.3), himbacine (7.2 +/- 0.2), pirenzepine (6.8 +/- 0.3) and methoctramine (6.2 +/- 0.2). These data are consistent with a role for Muscarinic M3 Receptors mediating contractions to oxotremorine M. The contractile response was associated with a low Receptor reserve, since the responses were shifted to the right and virtually abolished by the alkylating agent, 4-DAMP mustard (4-diphenylacetoxy-N-(2-chloroethyl) piperidine, 40 nM; 60 min equilibration). 3. In tissues precontracted with U46619 (0.7 microM; approx. EC90), isoprenaline (pEC50 = 8.0 +/- 0.1) and 5-HT (pEC50 = 7.5 +/- 0.2) induced concentration-dependent relaxations. The isoprenaline potency was slightly, but significantly, different in tissues precontracted with oxotremorine M (isoprenaline, pEC50 = 7.4 +/- 0.2). In contrast, the potency of 5-HT (pEC50 = 7.5 +/- 0.2), in tissues that were precontracted with 1 microM (EC90) oxotremorine M, was identical. When these experiments were repeated in the presence of the Muscarinic M2 Receptor antagonist, methoctramine (1 microM), there was no effect on the relaxant potencies to either 5-HT or isoprenaline. Collectively, these data suggest that Muscarinic M2 Receptors do not, under these conditions, modulate relaxant potencies to either 5-HT or isoprenaline. 4. In a second protocol, tissues were pre-contracted with U46619 (0.7 microM) and relaxed with either 5-HT (0.1 microM) or isoprenaline (0.1 microM). In these tissues (in which the Muscarinic M3 Receptor population was extensively depleted by alkylation), oxotremorine M caused concentration-dependent re-contractions (i.e. reversal of relaxations). In tissues relaxed with 5-HT, the potency of oxtremorine M was 5.9 +/- 0.2, while in tissues relaxed with isoprenaline, the potency (pEC50) = 5.6 +/- 0.3. These re-contractions were antagonized, in a surmountable fashion, by methoctramine (1 microM; pKB = 7.6 +/- 0.1). Similar observations were seen when relaxations were induced by isoprenaline (1 microM; pKB = 7.5 +/- 0.2). Under these conditions, therefore, the pKB values are consistent with activation of Muscarinic M2 Receptors, and inconsistent with activation of M3 Receptors. 5. It is concluded that in isolated oesophageal muscularis mucosae of rat, Muscarinic M3 Receptors mediate direct contractions and are associated with a low Receptor reserve. When this population is depleted, and the tissues relaxed via activation of Receptors that augment adenylyl cyclase activity, a functional role for Muscarinic M2 Receptors is revealed.
B Peelle - One of the best experts on this subject based on the ideXlab platform.
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functional interactions between Muscarinic M2 Receptors and 5 hydroxytryptamine 5 ht 4 Receptors and β adrenoceptors in isolated oesophageal muscularis mucosae of the rat
British Journal of Pharmacology, 1996Co-Authors: Richard M. Eglen, B Peelle, M T Pulidorios, E LeungAbstract:1. Relaxations of isolated oesophageal muscularis mucosae of rat are mediated by 5-hydroxytryptamine (5-HT), acting at 5-HT4 Receptors, and isoprenaline, principally acting via beta 3-adrenoceptors. The aim of this study was to investigate the hypothesis that Muscarinic M2 Receptors, also present in this tissue, functionally oppose 5-HT and beta-adrenoceptor-relaxant effects in this preparation. 2. Contractions of rat oesophageal muscularis mucosae were induced, in a concentration-dependent manner, by the Muscarinic Receptor agonist, oxotremorine M (pEC50 = 6.7 +/- 0.1). The contractile responses to oxotremorine M were surmountably antagonized by the following compounds, (pKB values in parentheses): atropine (9.1 +/- 0.2), 4-DAMP (4-diphenylacetoxy-N-methyl piperidine methiodide, 8.7 +/- 0.1), p-F-HHSiD (para-fluoro-hexa-hydro-siladifenidol, 7.5 +/- 0.1), zamifenacin (8.6 +/- 0.3), himbacine (7.2 +/- 0.2), pirenzepine (6.8 +/- 0.3) and methoctramine (6.2 +/- 0.2). These data are consistent with a role for Muscarinic M3 Receptors mediating contractions to oxotremorine M. The contractile response was associated with a low Receptor reserve, since the responses were shifted to the right and virtually abolished by the alkylating agent, 4-DAMP mustard (4-diphenylacetoxy-N-(2-chloroethyl) piperidine, 40 nM; 60 min equilibration). 3. In tissues precontracted with U46619 (0.7 microM; approx. EC90), isoprenaline (pEC50 = 8.0 +/- 0.1) and 5-HT (pEC50 = 7.5 +/- 0.2) induced concentration-dependent relaxations. The isoprenaline potency was slightly, but significantly, different in tissues precontracted with oxotremorine M (isoprenaline, pEC50 = 7.4 +/- 0.2). In contrast, the potency of 5-HT (pEC50 = 7.5 +/- 0.2), in tissues that were precontracted with 1 microM (EC90) oxotremorine M, was identical. When these experiments were repeated in the presence of the Muscarinic M2 Receptor antagonist, methoctramine (1 microM), there was no effect on the relaxant potencies to either 5-HT or isoprenaline. Collectively, these data suggest that Muscarinic M2 Receptors do not, under these conditions, modulate relaxant potencies to either 5-HT or isoprenaline. 4. In a second protocol, tissues were pre-contracted with U46619 (0.7 microM) and relaxed with either 5-HT (0.1 microM) or isoprenaline (0.1 microM). In these tissues (in which the Muscarinic M3 Receptor population was extensively depleted by alkylation), oxotremorine M caused concentration-dependent re-contractions (i.e. reversal of relaxations). In tissues relaxed with 5-HT, the potency of oxtremorine M was 5.9 +/- 0.2, while in tissues relaxed with isoprenaline, the potency (pEC50) = 5.6 +/- 0.3. These re-contractions were antagonized, in a surmountable fashion, by methoctramine (1 microM; pKB = 7.6 +/- 0.1). Similar observations were seen when relaxations were induced by isoprenaline (1 microM; pKB = 7.5 +/- 0.2). Under these conditions, therefore, the pKB values are consistent with activation of Muscarinic M2 Receptors, and inconsistent with activation of M3 Receptors. 5. It is concluded that in isolated oesophageal muscularis mucosae of rat, Muscarinic M3 Receptors mediate direct contractions and are associated with a low Receptor reserve. When this population is depleted, and the tissues relaxed via activation of Receptors that augment adenylyl cyclase activity, a functional role for Muscarinic M2 Receptors is revealed.
Maryrose P Sullivan - One of the best experts on this subject based on the ideXlab platform.
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the role of the mucosa in modulation of evoked responses in the spinal cord injured rat bladder
Neurourology and Urodynamics, 2018Co-Authors: Claire Doyle, Vivian Cristofaro, Bryan S Sack, Fabliha Mahmood, Maryrose P SullivanAbstract:AIMS Mounting evidence indicates that a variety of factors released from the urothelium or suburothelium can modulate smooth muscle activity. Although the relationship between the mucosa and smooth muscle has been investigated, little is known about the pathophysiologic changes in detrusor-mucosa interactions in neurogenic bladders. The goal of the study was to determine the impact of the mucosa on evoked responses in spinal cord injured (SCI) bladders. METHODS Urinary bladders were obtained from 6wk SCI rats or age-matched uninjured controls. Ex vivo isometric tension studies were performed and Muscarinic Receptor expression was measured in bladder tissue with and without mucosa. RESULTS The magnitude and area of nerve evoked responses in SCI tissue with mucosa was higher than without mucosa. The duration and decay time of nerve-evoked responses were longer in SCI than control tissue irrespective of the mucosa. The level of the Muscarinic M2 Receptor was decreased in the mucosa of SCI bladders. CONCLUSIONS Detrusor-mucosa interactions are substantially altered in the neurogenic bladder. After spinal cord injury, an excitatory modulation of smooth muscle contraction by the mucosa emerges, and could be targeted via intravesical treatment in the context of neurogenic bladder dysfunction.
